Three-way translocation involving MLL, MLLT1, and a novel third partner, NRXN1, in a patient with acute lymphoblastic leukemia and t(2;19;11) (p12;p13.3;q23).
Translocations involving mixed lineage leukemia (MLL) gene at 11q23 are associated with de novo acute leukemia as well as therapy-related acute leukemia. More than 100 different translocations involving MLL have been described in acute leukemia, with more than 60 translocation partner genes characterized on the molecular level. In addition to various simple translocations affecting MLL, there are also complex forms involving three or more chromosomes. Here, we describe a novel three-way translocation of t(2;19;11)(p12;p13.3;q23) in a patient with acute lymphoblastic leukemia (ALL). In this translocation, the distal 19p13.3 joins the proximal 11q23 on der(11), whereas the distal 11q23 is translocated to 2p12. Three-way translocations involving 11q23 are often difficult to detect with cytogenetic means alone. In the present case, however, the chromosomes involved in the three-way translocation were readily identifiable by GTG banding. The MLL-MLLT1 fusion products from the derivative chromosome 11 were detected by reverse transcriptase-polymerase chain reaction (RT-PCR), and two splicing variant forms were confirmed by cloning and sequencing. Furthermore, the novel third partner gene, NRXN1, was detected by systematic breakpoint analysis using long-distance inverse-PCR methods (LDI-PCR). The apparent three-way translocation thus identified is noteworthy because few studies have reported complex rearrangements involving 11q23 and 19p13.3 in acute leukemias.


Obesity in children and adolescents: understanding and treating the problem.
Childhood obesity is reviewed according to medical and sociological factors, psychological characteristics, family situations, and eating patterns. The treatment of obesity is reviewed according to different therapeutic modalities and the categories for provision of these services. There are indications that multicomponent programs, based on behavioral management principles, may offer the most effective treatment. Special emphasis is given to obesity treatment programs in school settings. There are many opportunities for social workers in health and other settings to provide vital services in preventing, alleviating, and treating the problem of childhood obesity.


Light absorption enhancement in thin silicon film by embedded metallic nanoshells.
Computer simulation studies of absorption enhancement in a silicon (Si) substrate by nanoshell-related localized surface plasmon resonance (LSPR) based on a finite-difference time-domain analysis are presented. The results of these studies show significant enhancement of over 15x in the near-bandgap spectral region of Si, using 40 nm diameter, two-dimensional silver (Ag) nanoshells, simulating cylindrical nanoshell structure. The studies also indicate a clear advantage of the cylindrical nanoshell structure over that of a completely filled Ag-nanocylinders. The enhancement was studied as a function of the metallic shell thickness. The results suggest that the main enhancement mechanism in this case of tubular nanoshells embedded in the Si substrate is that of field-enhanced absorption caused by the strong LSPR-enhanced electric field, extending into the silicon substrate.


Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses.
Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases.


Papillary fibroelastoma: echocardiographic characteristics for diagnosis and pathologic correlation.
We sought to determine the clinical and echocardiographic characteristics of papillary fibroelastoma (PFE). PFE is a rarely encountered cardiac tumor about which relatively little is known. Institutional records were reviewed for the years 1980 to 1995 for patients with pathologic or echocardiographic diagnosis of PFE. Group 1 included 17 patients with the pathologic diagnosis of PFE who also underwent echocardiography. Echocardiographic features of PFE were established in group 1. Group 2 included 37 patients with only echocardiographic evidence of PFE. In group 1, 7 (41.2%) of 17 patients had symptoms related to PFE. Neurologic events occurred in 5 (29.4%) of 17 patients. All patients had the tumor surgically removed. During follow-up, no new embolic events occurred. Echocardiographic characteristics of PFE included a small tumor (12.1 +/- 6.5 x 9.0 +/- 4.3 mm), usually pedunculated (14 [94%] of 17 patients) and mobile, with a homogeneous speckled pattern and a characteristic stippling along the edges. PFEs were most common on valvular surfaces (12 [60%] of 20 PFEs) but were not uncommon on other endocardial surfaces (8 [40%] of 20 PFEs). The tumor did not cause valvular dysfunction. In group 2, 16 (43%) of 37 patients were asymptomatic. Five patients (13.5%) had a previous neurologic event. During follow-up (mean 31 months, range 1 to 77), nine neurologic events occurred. PFEs are associated with embolism, can be diagnosed with echocardiography, are often an incidental clinical finding and do not cause valvular dysfunction.


The use of Chinese hamster ovary (CHO) cells in the study of ion channels.
The line of epithelial-like Chinese hamster ovary (CHO) cells was initiated by T.T. Puck in 1957. Since then, CHO cells have become a widely used mammalian expression system in industry and science. This paper discusses the different features of CHO cell physiology as well as the specific aspects of using these cells for ion channel studies; among the discussed features are the culturing and transfection of CHO cells, details of electrophysiological recordings from them and applications for the study of ion channel physiology and pharmacology. Examples of successful reconstitution of mammalian ion channels in CHO cells discussed in the paper include reconstitution of KCNQ channel regulation by muscarinic acetylcholine receptors and the study of the amiloride-sensitivity of epithelial sodium channels (ENaC).


Human Resource Information System implementation readiness in the Ethiopian health sector: a cross-sectional study.
Health workforce information systems in low-income countries tend to be defective with poor relationship to information sources. Human Resource Information System (HRIS) is currently in a pilot implementation phase in the Federal Ministry of Health and Regional Health Bureaus of Ethiopia. Before scaling up the implementation, it is important to understand the implementation readiness of hospitals and health departments. The aims of this study were to assess the readiness for HRIS implementation, identify associated factors, and explore the implementation challenges in public hospitals and health departments of the Amhara National Regional State, Ethiopia. An institution-based cross-sectional study supplemented with a qualitative study was conducted from the 15th of February to the 30th of March 2016 in 19 public hospitals and health departments of the Amhara National Regional State, Ethiopia. A self-administered questionnaire was used to collect the data. The questionnaire includes items on socio-demographic characteristics and questions measuring technical, personal, and organizational factors adapted from the 32-item questionnaire of the Management Science for Health (MSH) HRIS readiness assessment tool. The data were entered and analyzed with statistical software. Descriptive statistics and bivariate and multivariable logistic regression analyses were performed. Odds ratios with 95% confidence interval were computed to identify the factors statistically associated with readiness of HRIS implementation. In-depth interviews and observation checklists were used to collect qualitative data. Thematic content analysis was used to analyze the qualitative data. A total of 246 human resource (HR) employees and 16 key informants have been included in the study. The HR employee's level of readiness for HRIS implementation in this study was 35.8%. Employee's Internet access (AOR = 2.59, 95%CI = 1.19, 5.62), availability of separate HR section (AOR = 8.08, 95%CI = 3.69, 17.70), basic computer skills (AOR = 6.74, 95%CI = 2.75, 16.56), and fear of unemployment (AOR = 2.83, 95%CI = 1.27, 6.32) were associated with readiness of HRIS implementation. Poor logistic supply, lack of competency, poor commitment, and shortage of finance were the challenges of HRIS implementation. In this study, readiness of HRIS implementation was low. Strategies targeting to improve skills, awareness, and attitude of HR employees would facilitate the implementation process.


Control of Pseudomonas aeruginosa in the lung requires the recognition of either lipopolysaccharide or flagellin.
Acute lung infection due to Pseudomonas aeruginosa is an increasingly serious problem that results in high mortality especially in the compromised host. In this study, we set out to ascertain what components of the TLR system are most important for innate immunity to this microorganism. We previously demonstrated that TLR2,4-/- mice were not hypersusceptible to infection by a wild-type P. aeruginosa strain. However, we now find that mice lacking both TLR2 and TLR4 (TLR2,4-/- mice) are hypersusceptible to infection following challenge with a P. aeruginosa mutant devoid of flagellin production. We demonstrate that this hypersusceptibility is largely due to a lack of innate defense by the host that fails to control bacterial replication in the lung. Further evidence that a response to flagellin is a key factor in the failure of TLR2,4-/- mice to control the infection with the mutant strain was obtained by demonstrating that the intrapulmonary administration of flagellin over a 18 h period following infection, saved 100% of TLR2,4-/- mice from death. We conclude that the interactions of either TLR4 with LPS or TLR5 with flagellin can effectively defend the lung from P. aeruginosa infection and the absence of a response by both results in hypersusceptibility to this infection.


Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment.
The high mortality associated with the novel Middle East respiratory syndrome coronavirus (MERS-CoV) has raised questions about the possible role of a cytokine storm in its pathogenesis. Although recent studies showed that MERS-CoV infection is associated with an attenuated IFN response, no induction of inflammatory cytokines was demonstrated during the early phase of infection. To study both early and late cytokine responses associated with MERS-CoV infection, we measured the mRNA levels of eight cytokine genes [TNF-α, IL-1β, IL-6, IL-8, IFN-β, monocyte chemotactic protein-1, transforming growth factor-β and IFN-γ-induced protein (IP)-10] in cell lysates of polarized airway epithelial Calu-3 cells infected with MERS-CoV or severe acute respiratory syndrome (SARS)-CoV up to 30 h post-infection. Among the eight cytokine genes, IL-1β, IL-6 and IL-8 induced by MERS-CoV were markedly higher than those induced by SARS-CoV at 30 h, whilst TNF-α, IFN-β and IP-10 induced by SARS-CoV were markedly higher than those induced by MERS-CoV at 24 and 30 h in infected Calu-3 cells. The activation of IL-8 and attenuated IFN-β response by MERS-CoV were also confirmed by protein measurements in the culture supernatant when compared with SARS-CoV and Sendai virus. To further confirm the attenuated antiviral response, cytokine response was compared with human HCoV-229E in embryonal lung fibroblast HFL cells, which also revealed higher IFN-β and IP-10 levels induced by HCoV-229E than MERS-CoV at 24 and 30 h. Whilst our data supported recent findings that MERS-CoV elicits attenuated innate immunity, this represents the first report to demonstrate delayed proinflammatory cytokine induction by MERS-CoV. Our results provide insights into the pathogenesis and treatment of MERS-CoV infections.


Inorganic polyphosphates in mitochondria.
Current data concerning the crucial role of inorganic polyphosphates (polyP) in mitochondrial functions and dysfunctions in yeast and animal cells are reviewed. Biopolymers with short chain length (approximately 15 phosphate residues) were found in the mitochondria of Saccharomyces cerevisiae. They comprised 7-10% of the total polyP content of the cell. The polyP are located in the membranes and intermembrane space of mitochondria. The mitochondrial membranes possess polyP/Ca2+/polyhydroxybutyrate complexes. PolyP accumulation is typical of promitochondria but not of functionally active mitochondria. Yeast mitochondria possess two exopolyphosphatases splitting P(i) from the end of the polyP chain. One of them, encoded by the PPX1 gene, is located in the matrix; the other one, encoded by the PPN1 gene, is membrane-bound. Formation of well-developed mitochondria in the cells of S. cerevisiae after glucose depletion is accompanied by decrease in the polyP level and the chain length. In PPN1 mutants, the polyP chain length increased under glucose consumption, and the formation of well-developed mitochondria was blocked. These mutants were defective in respiration functions and consumption of oxidizable carbon sources such as lactate and ethanol. Since polyP is a compound with high-energy bonds, its metabolism vitally depends on the cell bioenergetics. The maximal level of short-chain acid-soluble polyP was observed in S. cerevisiae under consumption of glucose, while the long-chain polyP prevailed under ethanol consumption. In insects, polyP in the mitochondria change drastically during ontogenetic development, indicating involvement of the polymers in the regulation of mitochondrial metabolism during ontogenesis. In human cell lines, specific reduction of mitochondrial polyP under expression of yeast exopolyphosphatase PPX1 significantly modulates mitochondrial bioenergetics and transport.


Adiabatic circular polarizer based on chiral fiber grating.
Based on the adiabatic coupling principle, a new scheme of a broadband circular polarizer formed by twisting a high-birefringence (Hi-Bi) fiber with a slowly varying twist rate is proposed. The conditions of adiabatic coupling for the adiabatic polarizer are first identified through analytical derivations. These conditions are easily realized by choosing a reasonable variation of the twist rate. Moreover, the bandwidth of the polarizer is able to be directly determined by the twist rates at the two ends. Finally, the broadband characteristics of the polarizer are demonstrated by simulations. It is also shown that the performance of the polarizer can be remarkably improved by accomplishing a multi-mode phase-matching along the grating or by using of the couplings of the core mode to lossy modes.


T4 endonuclease involved in repair of DNA.
An enzyme activity, named T4 endonuclease V, was purified from T4-infected Escherichia coli. The enzyme induces single-stranded breaks in ultraviolet-irradiated DNA but does not act on native or heat-denatured DNA. The enzyme activity is dependent on the dose of ultraviolet irradiation, and the number of the breaks formed is approximately equal to the number of pyrimidine dimers present in the DNA. Denatured DNA, which has been exposed to ultraviolet light, is also attacked by the enzyme although the extent of the reaction is greater with irradiated native DNA. The enzyme shows optimal activity at pH 7.5 and does not require added divalent ions. When the enzyme-treated, irradiated DNA is subjected to stepwise degradation by spleen phosphodiesterase, dimers are released more rapidly than thymine into the acid-soluble fraction, suggesting that the enzyme induces a break at the 5'-side of a pyrimidine dimer. The enzyme, whose formation is controlled by the v(+) gene of T4, appears to be responsible for the first step of excision repair.


Prolonged sleep deprivation induces a cytokine-storm-like syndrome in mammals.
Most animals require sleep, and sleep loss induces serious pathophysiological consequences, including death. Previous experimental approaches for investigating sleep impacts in mice have been unable to persistently deprive animals of both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). Here, we report a "curling prevention by water" paradigm wherein mice remain awake 96% of the time. After 4 days of exposure, mice exhibit severe inflammation, and approximately 80% die. Sleep deprivation increases levels of prostaglandin D2 (PGD2) in the brain, and we found that elevated PGD2 efflux across the blood-brain-barrier-mediated by ATP-binding cassette subfamily C4 transporter-induces both accumulation of circulating neutrophils and a cytokine-storm-like syndrome. Experimental disruption of the PGD2/DP1 axis dramatically reduced sleep-deprivation-induced inflammation. Thus, our study reveals that sleep-related changes in PGD2 in the central nervous system drive profound pathological consequences in the peripheral immune system.


Diagnostic accuracy of helical CT arterial portography and CT hepatic arteriography for hypervascular hepatocellular carcinoma in chronic liver damage. An ROC analysis.
To evaluate the detectability of hypervascular hepatocellular carcinomas (HCCs) in chronic liver damage with helical CT arterial portography (CTAP) and CT hepatic arteriography (CTHA). Thirty-nine HCC patients who underwent CTAP and CTHA were studied. Diagnostic abilities of CTAP alone, CTHA alone, or combined CTAP and CTHA were evaluated by receiver operating characteristic (ROC) analysis. Fifty-three images with 53 HCC nodules were evaluated. Tumor size ranged from 5 to 90 mm (mean 22.8 mm). Sensitivities and specificities for all techniques were calculated. ROC analysis showed the diagnostic ability significantly better with combined CTAP and CTHA (mean area under the ROC curve (Az)=0.95), or CTHA alone (Az=0.93) than CTAP alone (Az=0.87) (p<0.01). Combined CTAP and CTHA showed the best sensitivity (95.0%), followed by CTHA alone (88.1%) and CTAP alone (85.5%). The specificities of all three imaging techniques were relatively low (54.1% for combined CTAP and CTHA, 71.1% for CTHA alone, and 54.1% for CTAP alone) because of perfusion abnormalities of the liver parenchyma. The combination of CTAP and CTHA is superior to CTAP alone for detection of hypervascular HCCs. However, its specificity was relatively low in chronic liver damage.


Efficiency of Protein Renewal Is Limited by Feed Intake and Not by Protein Lifetime in Aging Caenorhabditis elegans.
Protein turnover maintains the proteome's functional integrity. Here, protein turnover efficiency over time in wild-type Caenorhabditis elegans was assessed using inverse [15N]-pulse labeling up to 7 days after the egg-laying phase at 20 °C. Isotopic analysis of some abundant proteins was executed favoring data quality over quantity for mathematical modeling. Surprisingly, isotopic enrichment over time reached an upper limit showing an apparent cessation of protein renewal well before death, with protein fractions inaccessible to turnover ranging from 14 to 83%. For life span modulation, worms were raised at different temperatures after egg laying. Mathematical modeling of isotopic enrichment points either to a slowdown of protein turnover or to an increasing protein fraction resistant to turnover with time. Most notably, the estimated time points of protein turnover cessation from our mathematical model were highly correlated with the observed median life span. Thrashing and pumping rates over time were linearly correlated with isotopic enrichment, therefore linking protein/tracer intake to protein turnover rate and protein life span. If confirmed, life span extension is possible by optimizing protein turnover rate through modulating protein intake in C. elegans and possibly other organisms. While proteome maintenance benefits from a high protein turnover rate, protein turnover is fundamentally energy-intensive, where oxidative stress contributes to damage that it is supposed to repair.


Leveraging Collaborative Filtering to Accelerate Rare Disease Diagnosis.
In the USA, rare diseases are defined as those affecting fewer than 200,000 patients at any given time. Patients with rare diseases are frequently misdiagnosed or undiagnosed which may due to the lack of knowledge and experience of care providers. We hypothesize that patients' phenotypic information available in electronic medical records (EMR) can be leveraged to accelerate disease diagnosis based on the intuition that providers need to document associated phenotypic information to support the diagnosis decision, especially for rare diseases. In this study, we proposed a collaborative filtering system enriched with natural language processing and semantic techniques to assist rare disease diagnosis based on phenotypic characterization. Specifically, we leveraged four similarity measurements with two neighborhood algorithms on 2010-2015 Mayo Clinic unstructured large patient cohort and evaluated different approaches. Preliminary results demonstrated that the use of collaborative filtering with phenotypic information is able to stratify patients with relatively similar rare diseases.


Signal transduction during C. elegans vulval development: a NeverEnding story.
The Caenorhabditis elegans hermaphrodite vulva is one of the best studied models for signal transduction and cell fate determination during organogenesis. Systematic forward genetic screens have identified a complex and highly interconnected signaling network formed by the conserved EGFR, NOTCH, and WNT signaling pathways that specifies an invariant pattern of cell fates among the six vulval precursor cells (VPCs). Multiple inhibitory interactions between the EGFR and NOTCH pathways ensure the selection of a single 1° VPC that is always flanked by two 2° VPCs thanks to lateral NOTCH signaling. Building on this 'central dogma' of cell fate specification, scientists have investigated a broad spectrum of novel questions that are summarized in this review. For example, vulval development is a unique model to study the intracellular trafficking of signaling molecules, such as NOTCH or EGFR, to investigate the interactions between the cell cycle and cell fate specification pathways, and to observe epithelial tube morphogenesis and cell invasion at single-cell resolution. Finally, computer scientists have integrated the experimental data into mathematical and state-based 'in silico' models of vulval development, allowing them to test the completeness and limits of our current understanding.


Distributed Regression Analysis Application in Large Distributed Data Networks: Analysis of Precision and Operational Performance.
A distributed data network approach combined with distributed regression analysis (DRA) can reduce the risk of disclosing sensitive individual and institutional information in multicenter studies. However, software that facilitates large-scale and efficient implementation of DRA is limited. This study aimed to assess the precision and operational performance of a DRA application comprising a SAS-based DRA package and a file transfer workflow developed within the open-source distributed networking software PopMedNet in a horizontally partitioned distributed data network. We executed the SAS-based DRA package to perform distributed linear, logistic, and Cox proportional hazards regression analysis on a real-world test case with 3 data partners. We used PopMedNet to iteratively and automatically transfer highly summarized information between the data partners and the analysis center. We compared the DRA results with the results from standard SAS procedures executed on the pooled individual-level dataset to evaluate the precision of the SAS-based DRA package. We computed the execution time of each step in the workflow to evaluate the operational performance of the PopMedNet-driven file transfer workflow. All DRA results were precise (<10-12), and DRA model fit curves were identical or similar to those obtained from the corresponding pooled individual-level data analyses. All regression models required less than 20 min for full end-to-end execution. We integrated a SAS-based DRA package with PopMedNet and successfully tested the new capability within an active distributed data network. The study demonstrated the validity and feasibility of using DRA to enable more privacy-protecting analysis in multicenter studies.


Toxicological effects of acute and repeated doses (180 days) of fruits from Malpighia emarginata (acerola) in rodents.
Malpighia emarginata has a high amount of vitamin C with pharmacological or food preservation potential. However, despite its wide use and application possibilities its toxicity in repeated doses and for a long time (6 months) has not yet been studied. In this context, this study aimed to evaluate the acute toxicity and repeated doses from fruits of this plant. The extract was produced with the pulp (EMe) of the lyophilized fruit and submitted to chromatographic and spectroscopic analysis (HPLC and ESI-IT-MSn). In the acute test, the EMe was administered orally and parenterally to rodents (mice and rats) for 14 days, at a dose of 2000 mg/kg. Subsequently, the repeated dose toxicity test was administered orally for 180 days at doses of 50, 300 or 1000 mg/kg. The HPLC assay revealed a high concentration of vitamin C (16.3%), and spectroscopic analyses pointed to the presence of five other polyphenolic compounds. In the acute test, the plant extract showed no apparent toxicity or lethality in rodents. The LD50 was estimated to be greater than 2000 mg/kg and falls into category 5 (low toxicity). In the repeated dose assay, there was no evidence of toxicity, and no differences were observed in water intake, food, weight development, or behavior of the animals in relation to the vehicle group (water). However, hematological and biochemical evaluations pointed out some nonconformities in the levels of cholesterol, leukocytes, and neutrophils of the male rats, but overall, these results did not reveal significant toxicity. Therefore, the Level of Unobserved Adverse Effects (NOAEL) was 1000 mg/kg. Together, the results suggest that the extract obtained from the fruits of M. emarginata does not present representative toxicity in rodents.


Do hemodynamic studies of stage T1 lung cancer enable the prediction of hilar or mediastinal nodal metastasis?
We aimed to identify CT enhancement characteristics that predict hilar or mediastinal nodal metastasis in patients with stage T1 lung cancer. Eighty-four patients (50 men and 34 women; age range, 39-80 years; mean age, 61 years) with stage T1 lung cancer underwent a hemodynamic and a conventional morphologic CT study before curative surgical resection. Peak enhancement (maximum attenuation over the entire time course), net enhancement (peak enhancement minus preenhancement attenuation), maximum enhancement ratio (MER), time to peak enhancement, slope of enhancement on dynamic studies, nodule size, presence of tumor necrosis or thickening of bronchovascular bundles, and marginal characteristics on morphologic studies were analyzed and correlated with the presence of histologically determined mediastinal or hilar nodal metastasis. Mediastinal or hilar nodal metastases were found at surgery in 26 (31%) of 84 patients: mediastinal nodes in 13 (15%) and hilar nodes in 19 (23%). Six (7%) had both mediastinal and hilar nodal metastasis. Peak enhancement, net enhancement, and MER were significantly associated (p = 0.001, 0.002, and 0.008, respectively) with the presence of mediastinal or hilar nodal metastasis. A peak attenuation of 110 H or greater and a net enhancement of 60 H or greater predicted nodal metastasis with accuracies of 73% (61/84 nodules) and 73% (61/84 nodules) and odd ratios of 4.98 and 5.94, respectively. Stage T1 lung cancers showing peak enhancement of 110 H or greater or net enhancement of 60 H or greater on dynamic CT indicate a high likelihood of hilar or mediastinal nodal metastasis.


Multi-time point imaging in 99m Tc-pertechnetate scintigraphy of ectopic gastric mucosa in duplication cysts: value-added services.
The aim of our study was to describe the scintigraphic patterns of 99m Tc-pertechnetate uptake in patients who were referred to the department of nuclear medicine for evaluating and diagnosing ectopic gastric mucosa in foregut and midgut duplication cysts. This hospital-based, retrospective cum prospective research spans a period of 8 years from April 2014 to January 2022. Previous hospital medical records were analyzed and subsequently, a database was prepared which included the age, sex, clinical indication of a 99m Tc-pertechnetate scan, and the planar and SPECT-computed tomography (CT) imaging findings. Postoperative histopathological reports were available for 21 patients. Dynamic and planar static imaging was performed. We included SPECT-CT in suspected duplication cysts to increase the sensitivity and specificity which is a tradeoff for a small amount of additional radiation exposure. A total of 69 patients were subjected to a 99m Tc-pertechnetate scan for suspected foregut or midgut duplication cysts. All were subjected to dynamic planar and delayed static images up to 24 h or until focal uptake of radiotracer was noted which corroborated the anatomical findings, whichever was earlier. SPECT-CT was performed along with the planar study in 31 patients which confirmed the findings. Previously performed CT scans were used for anatomical correlation in the remaining ones. Duplication cysts were localized in a total of 28 patients (19 foregut duplication cysts and 12 small bowel duplications - 3 patients had dual duplication cysts, both foregut, and midgut). Forty-one patients had no scintigraphic evidence of ectopic gastric mucosa. Of these 69 patients, histopathological diagnosis was available for 21 patients (22 lesions). The report was concordant with the scan findings in 15 patients (16 lesions) and 6 patients showed discordance in histopathological diagnosis and scan findings. In conclusion, multi-time point imaging is the key to diagnosing ectopic gastric mucosa of various sizes and in various locations. An abnormal radiotracer uptake in dynamic sequences, even before the appearance of the stomach in the region of the small bowel is indicative of intestinal duplication, and delayed radiotracer visualization in the region of the thorax is characteristic of intrathoracic foregut duplication cyst.


A single lys residue on the first intracellular loop modulates the endoplasmic reticulum export and cell-surface expression of α2A-adrenergic receptor.
Export from the endoplasmic reticulum (ER) represents an initial step in intracellular trafficking of G protein-coupled receptors (GPCRs). However, the underlying molecular mechanisms remain poorly understood. We have previously demonstrated that a highly conserved Leu residue on the first intracellular loop (ICL1) is required for exit of several GPCRs from the ER. Here we found that, in addition to Leu64 residue in the ICL1, the neighboring positively charged residue Lys65also modulates the cell-surface transport of α(2A)-adrenergic receptor (α(2A)-AR). Mutation of Lys65 to Ala, Glu and Gln significantly attenuated, whereas mutation of Lys65 to Arg strongly augmented α(2A)-AR expression at the cell surface. Consistent with the effects on the cell-surface expression of α(2A)-AR, mutation of Lys65 to Ala and Arg produced opposing effects on α(2A)-AR-mediated ERK1/2 activation. Furthermore, confocal microscopy revealed that the α(2A)-AR mutant K65A displayed a strong intracellular expression pattern and was extensively co-localized with the ER marker DsRed2-ER, suggestive of ER accumulation. These data provide the first evidence indicating an important function for a single Lys residue on the ICL1 in the ER export and cell-surface expression of α(2A)-AR. These data also suggest that the ICL1 may possess multiple signals that control the cell-surface targeting of GPCRs via distinct mechanisms.


The course and quality of intimate relationships among psychologically distressed mothers.
The longitudinal course and quality of intimate relationships were tested in relation to maternal depressive symptoms in a sample of 1,275 families from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development. Assessments of mothers' intimate relationship status, intimate relationship quality, and depressive symptoms were obtained on 11 occasions from the birth of a child through age 15. Consistent with predictions, results from hierarchical linear models indicated that maternal depressive symptoms over time were associated with a lower probability of being married and lower levels of relationship quality. The strength of the association between relationship quality and depression was stronger than the linkage between relationship course and depression. Sociodemographic characteristics (e.g., mother age, child gender, ethnicity) were more predictive of trajectories of relationship course than relationship quality. Findings are discussed in terms of efforts to prevent and treat the longitudinal interplay between poor intimate relationship functioning and partners' psychopathology and its implications for the overall health and well-being of parents, couples, and children.


Possible roles of CXCL13/CXCR5 axis in the development of bullous pemphigoid.
CXCL13 recruits CXCR5+ follicular helper T (Tfh) cells in inflammatory lesions to develop secondary lymphoid organs. Tfh cells activate B cells to produce antibodies during humoral immune responses. Indeed, as previous reports suggested, CXCR5+ cell numbers were increased in the peripheral blood of bullous pemphigoid (BP) patients when compared with healthy donors, and the ratio of CXCR5+ cells was positively correlated with the anti-BP180-NC16A titers. From the above findings, in this report, we hypothesized that a chemokine related to CXCR5+ cells, namely CXCL13, may play a role in the development of BP. We performed immunohistochemical staining of CXCR5, CXCL13, LL37, CXCL10 and CCL20 for 10 cases of BP and 10 cases of pemphigus vulgaris (PV), and quantitatively analyzed the staining by digital microscopy. Moreover, we investigated the CXCL10 and CXCL13 production in BP and PV patients by enzyme-linked immunosorbent assay. The immunomodulatory effects of LL37 on the production of T-helper 17-related chemokines were evaluated using monocyte-derived M2 macrophages. Immunohistochemical staining and digital microscopic analysis showed that the ratios of CXCR5+ , CXCL13+ and LL37+ cells in the dermis were significantly higher in BP patients than in PV patients. Notably, the ratio of CXCL13+ cells was positively correlated with the anti-BP180-NC16A titers. Moreover, the serum levels of CXCL13 were positively correlated with the anti-BP180-NC16A titers. Furthermore, CD163+ M2 macrophages stimulated by LL37 in vitro produced CXCL10 and CCL20. In the lesional skin of BP, CD163+ macrophages CXCL10 and CCL20 were produced. The serum levels of CXCL10 were negatively correlated with the anti-BP180-NC16A titers. The present study results indicate that the mechanism of the development of BP may involve the CXCL13/CXCR5-mediated migration of Tfh cells.


[Behaviour of cellular immunity, detectable by means of intradermal test, following Toxoplasma gondii infection (author's transl)].
The percentage of strongly positive reactions to intradermal testing of 2,997 pregnant women was found to grown continuously by about one per cent per annum along with growing age. -- The conclusion drawn from comprehensive discussion of the above findings is that cellular immunity is likely to grow rather than decline, as assumed in the past, following toxoplasmosis infection. However, the increase, about one per cent annually, is of minor dimensions and might be based on a booster effect. -- This would mean, after all, that the intradermal test will continue to be of informative value, even long time after the infection, for example, in the context of aged patients. Therefore, no correction is required either by the criteria of interpretation.


Perifascial plane versus perineural approaches for ultrasound-guided axillary block: go to the simplest?
Ultrasound-guided axillary block is widely used in daily practice for upper limb orthopedic surgery. A simple, safe, efficacious and time-saving technique is mandatory to optimize surgical turnover and costs. In this perspective, we compared, in a randomized, single-blinded study, a standardized perifascial technique and the selective perineural technique. Forty-two patients scheduled for elective hand surgery were randomly assigned to receive 20 mL of 10 mg/mL mepivacaine, either selectively around each of the radial, median, ulnar and musculocutaneous nerves (perineural group) or along the latissimus dorsi and superficial axillary fascia (perifascial group). The primary outcome was the procedure performance time in both groups. Secondary goals were the number of needle passes, a per-procedure evaluation of the performance on a visual analogue scale ranging from 0 to 10, the success rate and the incidence of adverse events. Performance time was significantly reduced in the perifascial group (3.6 vs. 6.5 min, P<0.001), with fewer needle passes (3 vs. 6, P<0.001) and a simpler procedure performance (8.5 vs. 7.6, P=0.02). No vascular punctures or neurologic deficits were reported. Surgical anesthesia (95% in both groups) and complete anesthetic success (perifascial 81% vs. perineural 95%) were similar. We reported that the ultrasound-guided axillary perifascial block is easier to perform and saves procedural time compared to the classic perineural technique. Considering the same anesthetic success rate in both groups, the perifascial plane technique should be considered a daily practice technique and the first level of learning procedure for axillary block.


Age Patterns in Mental Representations of Time: Underlying Constructs and Relevant Covariates.
Research suggests that mental representations of time encompass multiple distinct aspects that vary with age, but prior studies rarely assessed more than one aspect of time perception and did not systematically consider relevant covariates. This lack of integration across studies hampers theory building and limits a deeper understanding of underlying constructs. Five widely used and conceptually distinct measures of time perception (i.e., perceived life position, global future horizons, future orientation and planning, self-continuity, and the temporal extension of episodic future thought) were administered to a demographically stratified adult life-span sample. Theoretically implicated covariates, including cognition, current affect, personality, and subjective health, were also assessed. Principle component analyses suggested a four-component solution. Perceived life position and global future horizons formed a single component reflecting subjective life span; the remaining measures each constituted separate components. The life span component and episodic future thought were negatively associated with age, self-continuity was positively associated with age, and future orientation did not vary by age. Among the covariates, mental and physical health showed the most pronounced associations with time perceptions, but the direction of effects varied across components. Findings suggest that mental representations of time encompass multiple components that show distinct age patterns and associations with covariates. Implications for theory building and practical applications are discussed.


Factors Associated With Management of Pediatric Ovarian Neoplasms.
Available evidence supports ovary-sparing surgery for benign ovarian neoplasms; however, preoperative risk stratification of pediatric ovarian masses can be difficult. Our objective of this study was to characterize the surgical management of pediatric ovarian neoplasms across 10 children's hospitals and to identify factors that could potentially aid in the preoperative risk stratification of these lesions. A retrospective review of girls and women aged 2 to 21 years who underwent surgery for an ovarian neoplasm between 2010 and 2016 at 10 children's hospitals was performed. Multivariable logistic regression was used to examine the relationships between the preoperative cohort characteristics, procedure performed, and risk of malignancy. Among 819 girls and women undergoing surgery for an ovarian neoplasm, malignant lesions were identified in 11%. The overall oophorectomy rate for benign disease was 33% (range: 15%-49%) across institutions. Oophorectomy for benign lesions was independently associated with provider specialty (P = .002: adult gynecologist, 45%; pediatric surgeon, 32%; pediatric gynecologist, 18%), premenarchal status (P = .02), preoperative suspicion for malignancy (P < .0001), larger lesion size (P < .0001), and presence of solid components (P < .0001). Preoperative findings independently associated with malignancy included increasing size (P < .0001), solid components (P = .003), and age (P < .0001). The rate of oophorectomy for benign ovarian disease remains high within the pediatric population. Identification of factors associated with the choice of procedure and the risk of malignancy may allow for improved preoperative risk stratification and fewer unnecessary oophorectomies. These results have been used to develop and validate a multidisciplinary preoperative risk stratification algorithm that is currently being studied prospectively across 10 institutions.


[Cleavage of tRNA and rRNA at 7-methylguanine in the presence of methylated carrier RNA].
A method of site-specific cleavage of some tRNAs and rRNAs at the 7-methylguanine residue is described. After reduction of 7-methylguanine by sodium borohydride treatment in the presence of the exogenous carrier RNA methylated statistically by dimethylsulfate the polynucleotide chain is cut at the modified residue by aniline. It was shown that the previously used procedure which did not involve a methylated carrier RNA is not applicable for splitting rRNAs or low concentrations of tRNAs. The method described was successfully used for site-specific cleavage of 32P-terminally labelled yeast tRNAPhe and unlabelled E. coli 16S rRNA at 7-methylguanine position.


Differential impact of post-deployment stress and PTSD on neural reactivity to emotional stimuli in Iraq and Afghanistan veterans.
For many veterans returning from combat in Iraq and Afghanistan, the transition from military to civilian life is complicated by an array of postdeployment stressors. In addition to significant stress associated with reintegration after deployment, many returning veterans also contend with the added burden conferred by PTSD symptoms. While the relationship between PTSD symptoms and the neurobiological substrates of emotion dysregulation has begun to be studied, even less is known about the effects of postdeployment stress on neural function. In order to assess the relationship among a neural measure of attention to emotion (i.e. the late positive potential; LPP), PTSD symptoms and postdeployment stressors, EEG was recorded and examined in a linear mixed model of 81 OEF/OIF/OND veterans. Results revealed a main effect for postdeployment stressors such that increased postdeployment stress was associated with a relatively enhanced LPP across all emotion types. There was also a main effect for PTSD symptoms such that greater symptoms were related to a relatively blunted LPP across all emotion types. Findings may have important implications for understanding how both current stress and PTSD symptoms affect motivated attention as measured by the LPP. Moreover, this work highlights the need to consider the effects of current stress, in addition to PTSD symptoms, on the functioning of returning veterans.


[Iatrogenic disease in the elderly: about two cases of tricyclics-induced renal failure].
Prostatic hyperplasia is a common condition in people over the age of 50 and its incidence increases with age. It gives particular cause for concern when it is symptomatic. Drugs with potential adverse effects on lower urinary tract can induce symptoms. Among those, anticholinergic drugs causing primary or secondary effects, such as tricyclics, are often associated with symptoms. These are contraindicated in patients with subvesical obstruction because they can induce or worsen urinary symptoms and complications resulting from them. Renal failure having health and economic consequences on elderly subjects Who often suffer from multiple disorders is the most severe complication. We report two cases of tricyclics-related adverse effects on the urinary tract in patients with prostatic hyperplasia ranging between 80 and 92 years. Given the lack of semiologic signs, imaging techniques and bladder TC scan enabled etiological diagnosis allowing adequate management. Study results justify a systematic performace of rectal examination, bladder CT scan or even ultrasound in any elderly with acute renal failure or with a worsening of chronic renal failure based on the frequency of prostatic pathologies and polypharmacy in this age.


Measurement invariance of brief forms of the Schizotypal Personality Questionnaire across convenience versus random samples.
Schizotypy, a multifaceted personality construct that represents liability for schizophrenia, is generally measured with self-report questionnaires that have been developed and validated in samples of undergraduate students. Given that understanding schizotypy in non-clinical samples is essential for furthering our understanding of schizophrenia-spectrum psychopathologies, it is critical to test whether non-clinically identified undergraduate and other convenience samples respond to schizotypy scales in the same way as random samples of the general population. Here, 651 undergraduates, 350 MTurk workers, and two randomly selected high school samples (n = 177, n = 551) completed brief versions of the Schizotypal Personality Questionnaire (SPQ-BR or SPQ-BRU). Multigroup confirmatory factor analysis was used to test whether measurement invariance was present across samples. Tests were made for all samples together and for each pair of samples. Results showed that a first-order nine-factor model fit the data well, and this factor structure displayed configural and metric invariance across the four samples. This suggests that schizotypy has the same factor structure, and the SPQ-BR/BRU is measuring the same construct across the different groups. However, when all groups were compared, results indicated a lack of scalar invariance across these samples, suggesting mean comparisons may be inappropriate across different sample types. However, when randomly selected high school students were compared with undergraduate students, scalar invariance was present. This suggests that factors such as culture and form type may be driving invariance, rather than sampling method (convenience vs general population).


Ambiguous diagnosis, futile treatments and temporary recovery: meanings of medical treatment among HIV/AIDS family caregivers providing care without ARVs.
The capacity of countries with high HIV and AIDS prevalence to provide antiretroviral treatment and care for all people who need support remains a public health challenge. In Lesotho, there are improvements in this area but the high proportion of people who need ART yet they do not receive treatment suggests that many HIV-infected people continue to depend on medicines that treat opportunistic infections. The objective of the article is to explore caregivers' experiences with diagnostic procedures and outcomes, prescriptions and treatment outcomes when ARVs were unavailable. A phenomenological design using in-depth face-to-face interviews was used to obtain the experiences of 21 family caregivers about caregiving, including access to and use of medical treatments. Caregivers' experiences indicate that most of the consulted health professionals provided vague and inconsistent diagnoses while the medication they prescribed failed to treat most of the symptoms. Unavailability of medicines that control pain and symptoms effectively continues to be a prominent feature of HIV and AIDS home-based caregiving in Lesotho. It is recommended that health professionals should facilitate disclosure of HIV diagnosis to family caregivers to assist them to understand unstable treatment outcomes; and policy makers should strengthen home-based care by developing policies that integrate palliative care into HIV and AIDS care.


Biochemical and clinical studies of aldolase isozymes in human cancer.
Radioimmunoassays specific for ALD isozymes were developed for the quantification of human ALD-A, -B, and -C. The method is a double antibody radioimmunoassay consisting of purified radioiodinated ALD-A, -B, and C as ligand, chicken antibodies to ALD-A, -B, and -C, and rabbit antibodies to chicken IgG. The Iodogen method was used for the iodination of the purified isozymes. ALD-A was present in high concentration in muscle, ALD-B in adult liver, and ALD-C in adult brain. ALD-A was elevated in hepatoma tissue and hepatoma cell lines, whereas ALD-B was distinctly low. Normal serum levels for the three isozymes were determined. The ALD-A level in the serum from 41 normal subjects was 170 +/- 39 ng/ml. Serum ALD-A level was increased in many patients with cancer and muscle diseases, but not in patients with hepatitis or other benign diseases. Serum ALD-B level in 11 normal subjects was 28.5 +/- 9.2 ng/ml. Serum ALD-C level in 12 normal subjects was 2.4 +/- 0.7 ng/ml. The determination of ALD-A, -B, and -C by radioimmunoassay may be a valuable tool in biochemical and clinical studies of these isozymes.


The putative (pro)renin receptor blocker HRP fails to prevent (pro)renin signaling.
The prorenin/renin receptor is a recently discovered component of the renin-angiotensin system. The effects of aliskiren, a direct inhibitor of human renin, were compared with the handle region decoy peptide (HRP), which blocks the prorenin/renin receptor, in double-transgenic rats overexpressing the human renin and angiotensinogen genes. After 7 wk, all aliskiren-treated rats were alive, whereas mortality was 40% in vehicle-treated and 58% in HRP-treated rats. Aliskiren but not the HRP reduced BP and normalized albuminuria, cystatin C, and neutrophil gelatinase-associated lipocalin, a marker of renal tubular damage, to the levels of nontransgenic controls. In vitro, human renin and prorenin induced extracellular signal-regulated kinase 1/2 phosphorylation, independent of angiotensin II (AngII), in vascular smooth muscle cells. Preincubation with the HRP or aliskiren did not prevent renin- and prorenin-induced extracellular signal-regulated kinase 1/2 phosphorylation, whereas the MAP kinase kinase (MEK1/2) inhibitor PD98059 prevented both. In conclusion, renin inhibition but not treatment with the HRP protects against AngII-induced renal damage in double-transgenic rats. In addition, the in vitro data do not support the use of the HRP to block AngII-independent prorenin- or renin-mediated effects.


Curcumin as Prospective Anti-Aging Natural Compound: Focus on Brain.
The nutrients and their potential benefits are a new field of study in modern medicine for their positive impact on health. Curcumin, the yellow polyphenolic compound extracted from Curcuma longa species, is widely used in traditional Ayurvedic medicine to prevent and contrast many diseases, considering its antioxidant, immunomodulatory, anti-inflammatory, anti-microbial, cardio-protective, nephron-protective, hepato-protective, anti-neoplastic, and anti-rheumatic proprieties. In recent years, the investigations of curcumin have been focused on its application to aging and age-associated diseases. Aging is a physiological process in which there is a decreasing of cellular function due to internal or external stimuli. Oxidative stress is one of the most important causes of aging and age-related diseases. Moreover, many age-related disorders such as cancer, neuroinflammation, and infections are due to a low-grade chronic systemic inflammation. Curcumin acting on different proteins is able to contrast both oxidative stress than inflammation. In the brain, curcumin is able to modulate inflammation induced by microglia. Finally in brain tumors curcumin is able to reduce tumor growth by inhibition of telomerase activity. This review emphasizes the anti-aging role of curcumin focusing on its mechanism to counteract aging in the brain. Moreover, new formulations to increase the bioavailability of curcumin are discussed.


Factors affecting Culicoides species composition and abundance in avian nests.
Mechanisms affecting patterns of vector distribution among host individuals may influence the population and evolutionary dynamics of vectors, hosts and the parasites transmitted. We studied the role of different factors affecting the species composition and abundance of Culicoides found in nests of the blue tit (Cyanistes caeruleus). We identified 1531 females and 2 males of 7 different Culicoides species in nests, with C. simulator being the most abundant species, followed by C. kibunensis, C. festivipennis, C. segnis, C. truncorum, C. pictipennis and C. circumscriptus. We conducted a medicationxfumigation experiment randomly assigning bird's nests to different treatments, thereby generating groups of medicated and control pairs breeding in fumigated and control nests. Medicated pairs were injected with the anti-malarial drug Primaquine diluted in saline solution while control pairs were injected with saline solution. The fumigation treatment was carried out using insecticide solution or water for fumigated and control nests respectively. Brood size was the main factor associated with the abundance of biting midges probably because more nestlings may produce higher quantities of vector attractants. In addition, birds medicated against haemoparasites breeding in non-fumigated nests supported a higher abundance of C. festivipennis than the rest of the groups. Also, we found that the fumigation treatment reduced the abundance of engorged Culicoides in both medicated and control nests, thus indicating a reduction of feeding success produced by the insecticide. These results represent the first evidence for the role of different factors in affecting the Culicoides infracommunity in wild avian nests.


Social genomics of healthy and disordered internet gaming.
To combine social genomics with cultural approaches to expand understandings of the somatic health dynamics of online gaming, including in the controversial nosological construct of internet gaming disorder (IGD). In blood samples from 56 U.S. gamers, we examined expression of the conserved transcriptional response to adversity (CTRA), a leukocyte gene expression profile activated by chronic stress. We compared positively engaged and problem gamers, as identified by an ethnographically developed measure, the Positive and Negative Gaming Experiences Scale (PNGE-42), and also by a clinically derived IGD scale (IGDS-SF9). CTRA profiles showed a clear relationship with PNGE-42, with a substantial linkage to offline social support, but were not meaningfully associated with disordered play as measured by IGDS-SF9. Our study advances understanding of the psychobiology of play, demonstrating via novel transcriptomic methods the association of negatively experienced internet play with biological measures of chronic threat, uncertainty, and distress. Our findings are consistent with the view that problematic patterns of online gaming are a proxy for broader patterns of biopsychosocial stress and distress such as loneliness, rather than a psychiatric disorder sui generis, which might exist apart from gamers' other life problems. By confirming the biological correlates of certain patterns of internet gaming, culturally-sensitive genomics approaches such as this can inform both evolutionary theorizing regarding the nature of play, as well as current psychiatric debates about the appropriateness of modeling distressful gaming on substance addiction and problem gambling.


Chemiluminescence-Based Assay to Monitor Early Oxidative Bursts in Soybean (Glycine max) Lateral Roots.
The reactive oxygen species (ROS) burst assay is a valuable tool for studying pattern-triggered immunity (PTI) in plants. During PTI, the interaction between pathogen recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs) leads to the rapid production of ROS in the apoplastic space. The resultant ROS can be measured using a chemiluminescent approach that involves the usage of horseradish peroxidase and luminol. Although several methods and protocols are available to detect early ROS bursts in leaf tissues, no dedicated method is available for root tissues. Here, we have established a reliable method to measure the PAMP-triggered ROS burst response in soybean lateral roots. In plants, lateral roots are the potential entry and colonization sites for pathogens in the rhizosphere. We have used important PAMPs such as chitohexaose, flagellin 22 peptide fragment, and laminarin to validate our method. In addition, we provide a detailed methodology for the isolation and application of fungal cell wall components to monitor the oxidative burst in soybean lateral roots. Furthermore, we provide methodology for performing ROS burst assays in soybean leaf discs with laminarin and fungal cell walls. This approach could also be applied to leaf and root tissues of other plant species to study the PTI response upon elicitor treatment. © 2023 Wiley Periodicals LLC. Basic Protocol: Reactive oxygen species (ROS) burst assay in soybean lateral root tissues Alternate Protocol: ROS burst assay in soybean leaf discs Support Protocol: Isolating fungal cell wall fractions.


Computed tomography in the management of orbital infections associated with dental disease.
Two patients developed orbital infection secondary to dental infections. In one patient the infection spread from maxillary premolar and molar teeth to the infratemporal and pterygopalatine fossa and then through the inferior orbital fissure to the subperiosteal space. A subperiosteal abscess in the posterior orbital wall developed, which subsequently spread within the muscle cone. In the second patient infection of an anterior maxillary tooth caused a pansinusitis and unilateral orbital cellulitis. In both patients computed tomographic scanning of the orbit proved valuable in localising the infection and, in one case, planning a surgical approach to the orbit. The infection in both patients responded to treatment, with no permanent visual impairment. Appropriate antibiotics and prompt identification and surgical drainage of orbital abscesses are essential for the preservation of vision in cases of orbital infection.


[Isolation and characteristics of staphylococcal alpha-toxin].
A method for isolation of staphylococcal alpha-toxin preparations has been elaborated. Characteristics of the toxin isolated by the method are as follows: mol. mass = 35 Kd; HU = 0.1 microgram; DnD= 0.1 microgram; LD50 = 2 micrograms. It is for the first time that alpha-toxin was fragmented by papain and digested by alpha, gamma-chemotrypsin. The papain fragments (18.5 and 15 Kd) retained lethal activity but lost hemolytic and dermonecrotic activities. Alpha, gamma-chemotryptic digested fragments (18 and 15 Kd) retained hemolytic and lethal effects, but lost their dermonecrotic activity.


A review of gene therapy in canine and feline models of lysosomal storage disorders.
Lysosomal storage disorders (LSDs) are inherited diseases that result from the intracellular accumulation of incompletely degraded macromolecules. The majority of LSDs affect both the peripheral and central nervous systems and are not effectively treated by enzyme replacement therapy, substrate reduction therapy, or bone marrow transplantation. Advances in adeno-associated virus and retroviral vector development over the past decade have resurged gene therapy as a promising therapeutic intervention for these monogenic diseases. Animal models of LSDs provide a necessary intermediate to optimize gene therapy protocols and assess the safety and efficacy of treatment prior to initiating human clinical trials. Numerous LSDs are naturally occurring in large animal models and closely reiterate the lesions, biochemical defect, and clinical phenotype observed in human patients, and whose lifetime is sufficiently long to assess the effect on symptoms that develop later in life. Herein, we review that gene therapy in large animal models (dogs and cats) of LSDs improved many manifestations of disease, and may be used in patients in the near future.


Patient Perceptions of Diabetes Guideline Frameworks for Individualizing Glycemic Targets.
Diabetes guidelines recommend considering specific factors, such as diabetes duration and life expectancy, to individualize treatment in older adults. These individualized glycemic targets inform decisions on whether to intensify or deintensify medication treatment plans. How older adults with diabetes perceive these factors used to individualize glycemic targets is unknown. To examine how older adults perceive factors used in diabetes guidelines for individualizing glycemic targets. A cross-sectional national survey was conducted from December 13, 2018, to January 3, 2019, of a nationally representative, probability-based online survey panel (KnowledgePanel). A total of 1364 KnowledgePanel members who were 65 years or older and had type 2 diabetes were invited to participate in the survey; 836 (61.3%) responded, and 818 (60.0%) completed the survey. The study randomized participants to 2 vignettes: one about adding and the other about removing diabetes medications from treatment plans. Participants rated the importance of 7 factors (diabetes duration, established diabetes complications, other health conditions, life expectancy, risk of adverse effects, cost, and treatment effort) in these treatment decisions using binary (yes/no) responses and the best-worst scaling method to quantify the factors' relative importance. All participants then answered questions on how different levels of each factor were associated with aggressiveness of diabetes treatment. The sample included 818 participants (mean [SD] age, 74.0 [6.8] years; 469 [53.7%] male; and 668 [67.7%] white). A total of 410 participants answered questions about adding medicine, whereas 408 participants answered questions about stopping medicine. Of the 7 factors to consider for adding a diabetes medication to the treatment plan, the number who deemed each factor important ranged from 197 (45.6%) to 263 (62.8%). In contrast, these same factors were considered important by only 29 (8.4%) to 146 (37.7%) of participants when deciding to stop use of a diabetes medication. In both decisions, participants perceived the risk of adverse effects as the most important factor (relative importance was 22.8 for adding a medicine and 25.0 for stopping a medicine on a ratio scale in which, for each decision, the relative importance of the 7 factors adds up to 100, with 0 indicating complete indifference and 100 complete priority). In contrast to current guideline recommendations, most participants believed that patients with longer disease duration (498 [60.1%]), more established complications (632 [75.6%]), and greater number of other health conditions (545 [67.5%]) should receive more aggressive diabetes treatment. Many older adults do not place high importance on factors recommended by guidelines to individualize diabetes treatment, especially when deciding to stop use of diabetes medications. Moreover, when considering treatment aggressiveness, many older adults weighted several factors in the opposite direction than suggested by the guidelines. Individualizing diabetes care in older adults will require effective communication regarding the benefits and consequences of making changes to treatment plans.


TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP.
The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap-/- macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap-/- myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components.


Silver nanowire decorated heatable textiles.
The modification of insulating fabrics with electrically conductive nanomaterials has opened up a novel application field. With the help of Joule heating mechanism, conductive fabrics can be used as mobile heaters. In this work, heatable textiles are fabricated using silver nanowires (Ag NWs). Cotton fabrics are decorated with polyol synthesized Ag NWs via a simple dip-and-dry method. The time-dependent thermal response of the fabrics under different applied voltages is investigated. It is found that the fabrics can be heated to 50 °C under an applied power density of as low as 0.05 W cm(-2). Uniform deposition of Ag NWs resulted in the homogeneous generation of heat. In addition, the stability of the fabrics with time and under different bending and washing conditions is examined. Moreover, a simple control circuit is fabricated and integrated in order to demonstrate the high potential of the fabrics for mobile applications. This work provides a roadmap for researchers who would like to work on heatable textiles with metallic NWs.


A role for adenosine in metabolic depression in the marine invertebrate Sipunculus nudus.
Involvement of neurotransmitters in metabolic depression under hypoxia and hypercapnia was examined in Sipunculus nudus. Concentration changes of several putative neurotransmitters in nervous tissue during anoxic or hypercapnic exposure or during combined anoxia and hypercapnia were determined. Among amino acids (gamma-aminobutyric acid, glutamate, glycine, taurine, serine, and aspartate) and monoamines (serotonin, dopamine, and norepinephrine), some changes were significant, but none were consistent with metabolic depression under all experimental conditions applied. Only the neuromodulator adenosine displayed concentration changes in accordance with metabolic depression under all experimental conditions. Levels increased during anoxia, during hypercapnia, and to an even greater extent during anoxic hypercapnia. Adenosine infusions into coelomic fluid via an indwelling catheter induced a significant depression of the normocapnic rate of O2 consumption from 0.36 +/- 0.04 to a minimum of 0.24 +/- 0.02 (SE) mumol.g-1.h-1 after 90 min (n = 6). Application of the adenosine antagonist theophylline caused a transient rise in O2 consumption 30 min after infusion during hypercapnia but not during normocapnia. Effects of adenosine and theophylline were observed in intact individuals but not in isolated body wall musculature. The results provide evidence for a role of adenosine in inducing metabolic depression in S. nudus, probably through the established effects of decreasing neuronal excitability and neurotransmitter release. In consideration of our previous finding that metabolic depression in isolated body wall musculature was elicited by extracellular acidosis, it is concluded that central and cellular mechanisms combine to contribute to the overall reduction in metabolic rate in S. nudus.


Coronary Sinus Thrombosis and Post-Myocardial Infarction Syndrome in Kawasaki Disease: Rare Causes of Pericardial Effusion.
The hypercoagulable state in Kawasaki disease (KD) may lead to complex cardiovascular sequelae. We present the case of a 2-month-old infant with complete KD complicated by giant coronary artery aneurysms, coronary sinus thrombosis, and post-myocardial infarction syndrome (Dressler syndrome), resulting in 2 distinct episodes of pericardial effusion. (Level of Difficulty: Intermediate.).


Reduced striatal tyrosine hydroxylase in incidental Lewy body disease.
Incidental Lewy body disease (ILBD) is the term used when Lewy bodies are found in the nervous system of subjects without clinically documented parkinsonism or dementia. The prevalence of ILBD in the elderly population has been estimated at between 3.8 and 30%, depending on subject age and anatomical site of sampling. It has been speculated that ILBD represents the preclinical stage of Parkinson's disease (PD) and/or dementia with Lewy bodies (DLB). Studies of ILBD could potentially identify early diagnostic signs of these disorders. At present, however, it is impossible to know whether ILBD is a precursor to PD or DLB or is just a benign finding of normal aging. We hypothesized that, if ILBD represents an early stage of PD or DLB, it should be associated with depletion of striatal dopaminergic markers. Eleven subjects with ILBD and 27 control subjects were studied. The ILBD subjects ranged in age from 74 to 96 years (mean 86.5) while the control subjects' age ranged from 75 to 102 years (mean 86.7). Controls and subjects did not differ in terms of age, postmortem interval, gender distribution, medical history conditions, brain weight, neuritic plaque density or Braak neurofibrillary stage. Quantitative ELISA measurement of striatal tyrosine hydroxylase (TH), the principal enzyme for dopamine synthesis, showed a 49.8% (P = 0.01) reduction in ILBD cases, as compared with control cases. The finding suggests that ILBD is not a benign condition but is likely a precursor to PD and/or DLB.


The different clinical facets of SYN1-related neurodevelopmental disorders.
Synapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1-related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1. In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment.


Local antibodies to alpha-casein and beta-lactoglobulin in the saliva of infants.
Salivary antibodies were studied in 112 infants between 1 day and 8 yr of life. SIgA anticasein was present from birth in breast-fed and bottle-fed infants. Bottle-feeding resulted in significantly higher concentrations of SIgA anticasein at 3 wk to 3 months of life as compared to breast-feeding. Salivary anticasein declined toward the end of the 1st yr and was present in less than half of the children older than 1 yr. Salivary anti-beta-lactoglobulin was also present at birth in some infants. Levels increased slightly over the following 3 months but remained low. Only a minority of older children had this antibody in their saliva.


Pituitary adenomas: current methods of diagnosis and treatment.
Pituitary adenomas are benign neoplasms that can be effectively managed by a variety of therapeutic options. The clinician's goal in managing patients with these tumors should be to minimize the morbidity of each intervention used in diagnosis and treatment. Standard diagnostic interventions include MRI, hormonal assessment, and tissue diagnosis. Therapies include transsphenoidal surgery, external-beam radiotherapy, newer stereotactic irradiation techniques, and medical management. Appropriate treatment selection requires detailed knowledge of the expected outcomes and side effects of each option. Newer and perhaps less toxic treatment techniques are evolving and require further evaluation.


[Additional magnesium therapy in tocolysis: clinico-chemical monitoring parameters].
Pregnancy can result in magnesium deficiency, which may precipitate premature labour usually reversed by betamimetic therapy. Inclusion of magnesium in tocolytic therapy is useful for possible reduction of premature labour as well as for cardioprotection. 35 patients with premature labour received Fenoterol + 20 mmol/day magnesium aspartate hydrochloride (Mg-asp-HCl) orally or 30 or 40 mmol/day Mg-asp-HCl and magnesium sulphate (MgSO4) (1:1) i.v. Before and during this therapy, Mg, Ca, K, Na, Cl, creatinin and urea as well as human placental lactogen (HPL) and oestriol (E3) were determined. There were no significant changes in the level of these under oral magnesium therapy. Under intravenous administration, plasma levels of magnesium rose significantly. In the following weeks, the levels dropped in spite of continuing the therapy. The other parameters showed no important changes. Under i.v. administration of 40 mmol/day Mg-asp-HCl, the HPL increase was highly significant. If this could be taken as a hint of better placental function such a positive side effect of magnesium therapy could prove beneficial to "small-for-age" foetuses. Co-medication of 20 mmol/day Mg-asp-HCl (oral) or 40 mmol/day Mg-asp-HCl and MgSO4 (1:1, i.v.) is recommended.


Inhibition of postprandial pancreatic and biliary secretion by loperamide in patients with short bowel syndrome.
Patients with the short bowel syndrome are usually afflicted by chronic diarrhoea and treated with opiate drugs, yet little documentation of the effects of such drugs on digestive function is available. In the present study we found that acute oral administration of loperamide resulted in 50% inhibition of postprandial trypsin and bilirubin output in patients with short bowel syndrome. These changes are consistent with an opiate effect.


Three-dimensional imaging in three-dimensional optical multi-beam micromanipulation.
In this work, we present a method providing real-time, low cost, three-dimensional imaging in a three-dimensional optical micromanipulation system. The three-dimensional imaging system is based on a small form factor LED based projector. The projector is used to dynamically shape the rear illumination light in a counter-propagating beam-trapping setup. This allows us to produce stereoscopic images, from which the human brain can construct a three-dimensional image, or alternatively image analysis can be applied by a computer, thereby obtaining true three-dimensional coordinates in real-time for the trapped objects.


Design rule of nanostructures in light-emitting diodes for complete elimination of total internal reflection.
Cone-shaped nanostructures with controllable side-wall angle are success- fully fabricated with a SiO(2) nanosphere lithography (NSL) etching mask. Vertical LEDs with cone-shaped nanostructures with a 24.1° side-wall angle provide 6% more light output power compared to those using hexagonal pyramids formed by photochemical etching. This achievement is attributed to effective elimination of total internal reflection by angle-controlled nanostructures.


Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.
The accurate identification and interpretation of germline mutations in mismatch repair genes in colorectal cancer cases is critical for clinical management. Current data suggest that mismatch repair mutations are highly heterogeneous and that many mutations are not detected when conventional DNA sequencing alone is used. To evaluate the potential of conversion analysis compared with DNA sequencing alone to detect heterogeneous germline mutations in MLH1, MSH2, and MSH6 in colorectal cancer patients. Multicenter study with patients who participate in the Colon Cancer Family Registry. Mutation analyses were performed in participant samples determined to have a high probability of carrying mismatch repair germline mutations. Samples from a total of 64 hereditary nonpolyposis colorectal cancer cases, 8 hereditary nonpolyposis colorectal cancer-like cases, and 17 cases diagnosed prior to age 50 years were analyzed from June 2002 to June 2003. Classification of family members as carriers or noncarriers of germline mutations in MLH1, MSH2, or MSH6; mutation data from conversion analysis compared with genomic DNA sequencing. Genomic DNA sequencing identified 28 likely deleterious exon mutations, 4 in-frame deletion mutations, 16 missense changes, and 22 putative splice site mutations. Conversion analysis identified all mutations detected by genomic DNA sequencing--plus an additional exon mutation, 12 large genomic deletions, and 1 exon duplication mutation--yielding an increase of 33% (14/42) in diagnostic yield of deleterious mutations. Conversion analysis also showed that 4 of 16 missense changes resulted in exon skipping in transcripts and that 17 of 22 putative splice site mutations affected splicing or mRNA transcript stability. Conversion analysis provided an increase of 56% (35/63) in the diagnostic yield of genetic testing compared with genomic DNA sequencing alone. The data confirm the heterogeneity of mismatch repair mutations and reveal that many mutations in colorectal cancer cases would be missed using conventional genomic DNA sequencing alone. Conversion analysis substantially increases the diagnostic yield of genetic testing for mismatch repair mutations in patients diagnosed as having colorectal cancer.


Physical education teachers' attitudes towards children with intellectual disability: the impact of time in service, gender, and previous acquaintance.
This study investigated attitudes towards teaching students with intellectual disability (ID) within a representative sample of secondary school physical education (PE) teachers, and to determine the effects of age, gender, teaching experience, and having acquaintance with ID and students with ID on their attitudes. Participants were 729 secondary school PE teachers who worked in 81 major cities of Turkey. The Teachers Attitudes towards Children with Intellectual Disability Scale was administered. The statistical analysis revealed that there was no significant effect on factors and total attitudes scores of gender and having students with ID. Significant effects on factors and total attitudes score were found in teaching experiences and having acquaintance with ID. It is encouraged to maintain and further develop in-service education programmes of adapted physical activity for PE teachers.


[Clinical reasoning--the diagnostic and therapeutic decision process].
The goal of this review is to demonstrate the steps and the main items of the cognitive process used by doctors in clinical reasoning of diagnostic and therapeutic decisions. The clinical problem-solving process makes use of the hypothetic deductive scientific method to solve problems. As soon as the doctor meets his (her) patient, many diagnostic hypotheses emerge in his (her) mind, which are evaluated and refuted or corroborated. The diagnostic decision occurs when a hypothesis reach a certain degree of likelihood. The therapeutic decision is based on the intended objectives and the waited effectiveness among many available alternatives.


Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans.
Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the congenital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans.


Analysis of chemotherapy response programs in ovarian cancers by the next-generation sequencing technologies.
To understand the chemotherapy response program in ovarian cancer cells at deep transcript sequencing levels. Two next-generation sequencing technologies--MPSS (massively parallel signature sequencing) and SBS (sequencing by synthesis)--were used to sequence the transcripts of IGROV1 and IGROV1-CP cells, and to sequence the transcripts of a highly chemotherapy responsive and a highly chemotherapy resistant ovarian cancer tissue. We identified 3422 signatures (2957 genes) that are significantly different between IGROV1 and IGROV1-CP cells (P<0.001). Gene Ontology (GO) term GO:0001837 (epithelial-to-mesenchymal transition) and GO:0034330 (cell junction assembly and maintenance) are enriched in genes that are over expressed in IGROV1-CP cells while apoptosis-related GO terms are enriched in genes over expressed in IGROV1 cells. We identified 1187 tags (corresponding to 1040 genes) that are differentially expressed between the chemotherapy responsive and the persistently chemotherapy resistant ovarian cancer tissues. GO term GO:0050673 (epithelial cell proliferation) and GO:0050678 (regulation of epithelial cell proliferation) are enriched in the genes over expressed in the chemotherapy resistant tissue while the GO:0007229 (integrin-mediated signaling pathway) is enriched in the genes over expressed in the chemotherapy sensitive tissue. An integrative analysis identified 111 common differentially expressed genes including two bone morphogenetic proteins (BMP4 and BMP7), six solute carrier proteins (SLC10A3, SLC16A3, SLC25A1, SLC35B3, SLC7A5 and SLC7A7), transcription factor POU5F1 (POU class 5 homeobox 1), and KLK10 (kallikrein-related peptidase 10). A network analysis revealed a subnetwork with three genes BMP7, NR2F2 and AP2B1 that were consistently over expressed in the chemoresistant tissue or cells compared to the chemosensitive tissue or cells. Our database offers the first comprehensive view of the digital transcriptomes of ovarian cancer cell lines and tissues with different chemotherapy response phenotypes.


Sexual reorientation therapy: an orthodox perspective.
This article evaluates the phenomenon of sexual reorientation therapy from the standpoint of Orthodox Christian theology. It is argued that homosexual desire is the product of the fall of mankind and cannot be considered "normal." At the same time, however, reorientation therapies, whether secular or Christian, are inherently reductionistic and fail to address the underlying spiritual pathologies involved in homosexual desire (or any other deep-seated passion). The purpose of therapeia in the Orthodox Church is the psycho-somatic transfiguration of the whole person into the image of Christ, not merely the cessation of homosexual activity or the "reidentification" of one's "lifestyle."


Quantitative morphology of permeability lung edema in dogs induced by alpha-naphthylthiourea.
In pulmonary edema, fluid accumulates first in the interstitium, then in the alveoli. However, the relative amounts of interstitial fluid around arteries and veins of different sizes are unknown; in addition, the effects of fixation on the light microscopic quantitation of edema are unclear. To answer these questions, we induced permeability pulmonary edema in seven anesthetized dogs with 27 mg/kg of alpha-naphthylthiourea. Pulmonary artery and wedge pressures were measured. After moderately severe edema, diagnosed by chest x-ray and falling arterial pO2, lobes were fixed by airways instillation or vascular perfusion with glutaraldehyde and formaldehyde or were frozen with liquid nitrogen. With light microscopy, the edema surrounding arteries and veins of different sizes was measured using a computer equipped with a digitizing tablet and expressed as the edema ratio = area of perivascular edema/area of vessel, or as an absolute area of edema. Alveolar edema was graded semiquantitatively, and wet weight to dry weight ratios were calculated. Two control dogs were also studied. During the induction of edema, pulmonary artery and wedge pressures did not change significantly. Mean wet weight to dry weight ratios were 9.3 +/- 1.1. We found that the edema ratio was greater (p less than 0.01) for arteries (2.75, n = 1305) than for veins (1.40, n = 900). The edema ratio was greater for vessels more than 400 micron than less than 400 micron (p less than 0.01) and greater in the instillation- and perfusion-fixed lobes than in the frozen lobes (p less than 0.01). Similar results were obtained for the absolute areas of periarterial and perivenous edema. Less alveolar edema was seen in the lobes fixed by instillation (p less than 0.01). We conclude that, in permeability edema induced by alpha-naphthylthiourea, the fluid accumulates preferentially around arteries compared with veins and around larger compared with smaller vessels. Airways instillation and vascular perfusion fixation appeared to increase interstitial fluid cuffs compared to freezing.


Infectivity of a Cryptosporidium parvum isolate of cervine origin for healthy adults and interferon-gamma knockout mice.
The infectivity of a Cryptosporidium parvum isolate of cervine origin (type 2, Moredun) propagated in calves was investigated simultaneously in healthy adult human volunteers and in interferon-gamma knockout (GKO) mice. After exposure to 100-3000 oocysts, 16 volunteers recorded, for a duration of 6 weeks, the number and form of stools that they passed and any symptoms that they experienced. Oocyst excretion was assessed by enzyme-linked immunosorbent assay and direct immunofluorescence assay. Eleven subjects (69%) became ill, and 8 subjects (50%) shed oocysts in stool. The median duration of illness was 169 h, and the median number of unformed stools passed was 24. The duration and intensity of symptoms were more severe than were those associated with previously studied isolates. The median infectious dose was estimated to be 300 oocysts for humans and 1 oocyst for the GKO mouse model. The Moredun isolate was more pathogenic than the reference GCH-1 isolate. The GKO mouse model of cryptosporidiosis is useful for discerning isolate-specific differences in pathogenicity.


Emergency and elective surgical treatment of portal hypertension. A review of 23 years' experience.
A retrospective review of surgical treatment for portal hypertension during a 23-year period in a regional unit is reported and the immediate and subsequent management of patients with bleeding oesophageal varices is discussed. Fifty-four patients with recurrent varix haemorrhage uncontrolled by conservative methods have been treated by oesophageal transection with a mortality of 22.2% (26.6% for cirrhotic patients). Thirty-two per cent of the cirrhotics were alive after 2 years. Only a minority (12%) of the survivors were considered suitable for a subsequent shunt procedure. Therapeutic portacaval anastomosis has been performed on 65 patients with a 51.2% 5-year survival (43-5% for cirrhotic patients). Further haemorrhage due to shunt thrombosis occurred in 5-3% of cases. The frequent occurrence of portal-systemic encephalopathy, increasing with duration of time following a shunt, is emphasized. The high morbidity and mortality in the poor-risk cirrhotic indicated that this type of patient is unsuitable for a portal-systemic shunt and is better treated by medical means.


Fluid Resuscitation with 5% albumin versus Normal Saline in Early Septic Shock: a pilot randomized, controlled trial.
Randomized, controlled trials of fluid resuscitation in early septic shock face many logistic challenges. We describe the Fluid Resuscitation with 5% albumin versus Normal Saline in Early Septic Shock (PRECISE) pilot trial study design and report feasibility of patient recruitment. Six Canadian academic centers enrolled adult patients with early suspected septic shock from the emergency department and intensive care unit department. Consent was deferred. Using concealed allocation, participants were randomized to either 5% albumin or 0.9% sodium chloride. Blinded fluid resuscitation started immediately and continued for 7 days in the intensive care unit. Target recruitment was established a priori at 2 patients per site per month. Fifty-one patients were enrolled; 50 patients received study fluid. We recruited a median of 2.5 patients (interquartile range [IQR], 1.5-3.0) per site per month into the trial. Median age and Acute Physiology and Chronic Health Evaluation II scores were 64.5 (IQR, 55.0-78.0) and 25.0 (IQR, 20.0-29.0), respectively. Most patients (n = 37 [74.0%]) were enrolled from the emergency department for a median of 1.6 hours (IQR, 0.8-3.5 hours) from their first hypotensive event and received a median of 2.4 L (IQR, 1.5-3.0 L) of resuscitation fluid before inclusion. Consent was deferred for 44 patients (89.8%). Patient recruitment into the PRECISE pilot trial met our prespecified feasibility targets, and the PRECISE team is planning the larger trial.


Cost-Effectiveness of Cetuximab for Advanced Esophageal Squamous Cell Carcinoma.
Costly biologicals in palliative oncology are emerging at a rapid pace. For example, in patients with advanced esophageal squamous cell carcinoma addition of cetuximab to a palliative chemotherapy regimen appears to improve survival. However, it simultaneously results in higher costs. We aimed to determine the incremental cost-effectiveness ratio of adding cetuximab to first-line chemotherapeutic treatment of patients with advanced esophageal squamous cell carcinoma, based on data from a randomized controlled phase II trial. A cost effectiveness analysis model was applied based on individual patient data. It included only direct medical costs from the health-care perspective. Quality-adjusted life-years and incremental cost-effectiveness ratios were calculated. Sensitivity analysis was performed by a Monte Carlo analysis. Adding cetuximab to a cisplatin-5-fluorouracil first-line regimen for advanced esophageal squamous cell carcinoma resulted in an the incremental cost-effectiveness ratio of €252,203 per quality-adjusted life-year. Sensitivity analysis shows that there is a chance of less than 0.001 that the incremental cost-effectiveness ratio will be less than a maximum willingness to pay threshold of €40,000 per quality-adjusted life-year, which is representative for the threshold used in The Netherlands and other developed countries. Addition of cetuximab to a cisplatin-5-fluorouracil first-line regimen for advanced esophageal squamous cell carcinoma is not cost-effective when appraised according to currently accepted criteria. Cost-effectiveness analyses using outcome data from early clinical trials (i.c. a phase II trial) enable pharmaceutical companies and policy makers to gain early insight into whether a new drug meets the current eligibility standards for reimbursement and thereby potential admittance for use in regular clinical practice.


Gastrulation in zebrafish: what mutants teach us.
A major approach to the study of development is to compare the phenotypes of normal and mutant individuals for a given genetic locus. Understanding the development of a complex metazoan therefore requires examination of many mutants. Relatively few organisms are being studied this way, and zebrafish is currently the best example of a vertebrate for which large-scale mutagenesis screens have successfully been carried out. The number of genes mutated in zebrafish that have been cloned expands rapidly, bringing new insights into a number of developmental pathways operating in vertebrates. Here, we discuss work on zebrafish mutants affecting gastrulation and patterning of the early embryo. Gastrulation is orchestrated by the dorsal organizer, which forms in a region where maternally derived beta-catenin signaling is active. Mutation in the zygotic homeobox gene bozozok disrupts the organizer genetic program and leads to severe axial deficiencies, indicating that this gene is a functional target of beta-catenin signaling. Once established, the organizer releases inhibitors of ventralizing signals, such as BMPs, and promotes dorsoanterior fates within all germ layers. In zebrafish, several mutations affecting dorsal-ventral (D/V) patterning inactivate genes functioning in the BMP pathway, stressing the central role of this pathway in the gastrula embryo. Cells derived from the organizer differentiate into several axial structures, such as notochord and prechordal mesoderm, which are thought to induce various fates in adjacent tissues, such as the floor plate, after the completion of gastrulation. Studies with mutants in nodal-related genes, in one-eyed pinhead, which is required for nodal signaling, and in the Notch pathway reveal that midline cell fate specification is, in fact, initiated during gastrulation. Furthermore, the organizer coordinates morphogenetic movements, and zebrafish mutants in T-box mesoderm-specific genes help clarify the mechanism of convergence movements required for the formation of axial and paraxial mesoderm.


Assessing the effects of drought on rainfed maize water footprints based on remote sensing approaches.
Drought affects the characteristics of water use during crop production and so quantitatively evaluating the impacts is important. However, it remains unclear how crop water use responds to drought. To address this gap, water footprint (WF) and standardized precipitation evapotranspiration index (SPEI) were calculated by remote sensing approaches to assess the effects of drought on crop water use. Rainfed maize is the most important crop in Jilin Province, and its growth and water use are more susceptible to drought. The present study explored not only the impact of growing season drought on the maize WF values in Jilin Province, but also the response of WF values to drought at different time scales. Spatially, 72.94% of the WFblue pixels showed a non-significant increase, and the WFgreen in 68% pixels decreased significantly, being mainly concentrated in the middle region. Furthermore, the pixels affected by monthly time scale drought were mainly in the middle region, whereas the pixels affected by annual time scale drought were mainly in the western region. Drought not only affected on the source and structure of agricultural water consumption, but also had different effects on WF values at different time scale. These effects had obvious spatial differences. The present study systematically explored the effects of drought on the WF values for rainfed maize in different climate regions and a consideration of these effects could provide valuable information on rainfed maize growth and the agricultural water use response to a changing climate. © 2023 Society of Chemical Industry.